TRPM8 is an integral membrane protein ion channel that functions as the primary cold sensor in higher organisms. Beyond its role as a cold sensor, TRPM8 has also been implicated in additional fundamental processes including pain and obesity. TRPM8 is regulated by a variety of chemical and physical stimuli, including direct interactions with lipids, such as the phosphoinositide lipid PI(4,5)2 Additionally, TRPM8 function is further modulated by the membrane protein PIRT (Phosphoinositide-Interacting Regulator or TRPs) which also has a PI(4,5)P2 binding site. To better understand the interactions between regulatory lipids in TRPM8 and the ternary TRPM8/PIRT/PI(4,5)P2 complex we have employed a mixture of experimental and computational techniques. Microscale thermophoresis (MST) and solution NMR binding studies identify how PIRT interacts with PI(4,5)P2 and a TRPM8 membrane domain in a competitive manner. Using Rosetta Membrane computational techniques we have generated comparative models of TRPM8 PI(4,5)P2 lipid interactions. Taken together, our data support a lipid shuttling–sequestering mechanism that regulates the TRPM8–PIRT membrane protein complex.

Phosphoinositide lipid interaction studies between TRPM8 and PIRT membrane proteins suggest a lipid shuttling–sequestering regulatory mechanism

2019 Spring National Meeting

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